A wound is a type of injury and can be divided into an open wound where skin is torn, punctured or cut and a closed wound such as a bruise, contusion, etc. caused by blunt force. There are various methods for treating wounds. When the wound is slight, it is healed naturally only by cleaning; however, when the wound is a serious open wound, it needs treatment such as cleaning, disinfection, suture and dressing. In the case of most clean open wounds, they do not require antibiotic treatment, but a wound that may be infected with bacteria or an infected wound requires antibiotic treatment.
The wound healing process involves a hemostasis phase including vasoconstriction and hemostatic chain reaction, an inflammatory phase in which immune-related cells are activated, a proliferation phase in which damaged blood vessels are newly formed and fibroblasts are formed, and a maturation and rearrangement phase in which disorganized collagen fibers are rearranged and cross-linked. When a wound occurs, blood comes in contact with collagen to promote platelet aggregation and secretion of inflammatory substances. Fibrin and fibronectin are cross-linked to form a sort of plug, preventing further blood loss. Within an hour after the wound occurs, polymorphonuclear neutrophils arrive at the wound site and become predominant cells in the wound after two days. These neutrophils phagocytize debris and bacteria in the wound. Macrophages are essential for wound healing and replace polymorphonuclear neutrophils the predominant cells in the wound by two days after injury. The main role of these macrophages is to phagocytize bacteria and damaged tissue and they also debride damaged tissue by releasing proteases. These macrophages also secrete growth factors involved in the proliferation phase after post-wounding, contributing to pushing the wound healing process into the next phase. About two or three days after the wound occurs, fibroblasts begin to enter the wound site, marking the onset of the proliferative phase. Angiogenesis, which is important for this period, occurs concurrently with fibroblast proliferation when endothelial cells migrate to the wound site. Simultaneously with angiogenesis, fibroblasts begin accumulating in the wound site. Fibroblasts begin to increasing as the inflammatory phase is ending between two and five days after the wound. Their numbers peak between one and two weeks after wound. While one of the most important functions of such fibroblasts is the production of collagen, the production of collagenase and other factors degrading collagen is also one of their functions, and the production occurs more rapidly than the degradation in the wound. Granulation tissue consists of fibroblasts, inflammatory cells, endothelial cells, new blood vessels, etc. The formation of granulation tissue in an open wound allows the reepithelialization phase to take place, as epithelial cells migrate and form a barrier between the wound and the environment. Contraction is a key phase of wound healing and begins as fibroblasts differentiate into myofibroblasts. When the levels of collagen production and degradation equalize, the maturation and rearrangement phase of wound repair is started. During maturation, type III collagen is gradually replaced with type I collagen, and fibroblasts are rearranged and cross-linked, resulting in increased tissue tension. This phase can last for a year or longer as the wound type.
Wound treatment methods have been studied for a long time and a variety of products have been sold in the market. Disinfecting products containing oxygenated water, povidone-iodine, ethyl alcohol, isopropyl alcohol, etc. used to disinfect the wound surface and dressing products such as gauze, bandage, etc. which facilitate hemostasis and protect the wound surface to prevent secondary infections, etc. have been sold. Moreover, products containing antibiotics, such as mupirocin, fusidic acid and salts thereof, tyrothricin, etc., used for a wound that may concern infection or be infected from such wound, or products containing a titrated extract of Centella asiatica alone or in combination with steroid or antibiotics have been sold usually in the form of a gel or ointment. Representative products include Fucidin® ointment, Tyrosur® gel, Madecassol®, etc.
The use of these gel or ointment formulations has the following several problems. Upon application to the wound, the formulation on the wound surface is not present for a long time due to external contact with gauze, clothing, etc. Therefore, the drug is not in constant contact with the wound surface and thus is not continuously delivered to the wound. Moreover, when the wound is exposed to the outside through the area from which the drug is removed, the probability of re-infection will increase. Further, the exposed wound causes the patient to feel pain by other external physical stimuli. Therefore, many patients use disposable bandage, gauze or bandage in combination with the use of these formulations to cope with these drawbacks, but it is very inconvenient to replace these dressings for each application. In addition, typical products containing antibiotics alone exhibit antibiotic activity in infected wound sites and thus they only prevent infection in infected wound sites. However, the effect of promoting wound healing that make a swift recovery is not yet known.
Therefore, the present inventors have conducted continuous research to overcome the drawbacks of the above-described preparations. As a result, they invented a wound healing gel, which is usually in the form of a gel during storage and usage, converted into the form of a film upon application to a wound site to protect the wound site, continuously deliver drugs to the wound site, and is not removed from the wound site by clothing, gauze, etc.
Several formulations containing pharmaceutical ingredients as active ingredients and forming films upon application to the skin have been known in the art. Korean Patent No. 0551930, Korean Patent Publication No. 2008-0049797 and Korean Patent No. 1996-0009415 disclose compositions comprising active substances as well as hydrophilic thickeners, hydrophobic polymers such as octylacrylamide acrylate copolymer, aminoalkyl methacrylate copolymer, ammonio methacrylate copolymer, ethyl acrylate methyl methacrylate, and volatile solvents such as ethanol. However, these compositions are separated with exudates after the formation of films on the wounds due to the high content of hydrophobic polymers and stimulate the wound surfaces due to the high content of organic solvents and thus these compositions are not suitable for wound healing. Moreover, Korean Patent No. 0979347 discloses an antifungal composition comprising terbinafine or a salt thereof and trimethyloxysilicate for forming a film after application to the skin. However, this composition is not also suitable for wound healing due to the above-described problems such as the high content of hydrophobic substance and organic solvent.
Korean Patent No. 0748390 discloses a sustained release film formulation for wound healing comprising epidermal growth factor as well as chitosan, glycerin, etc. However, this technology reduces the adhesion between the wound and the formulation, because it does not form a film directly on the wound surface. Therefore, the drug delivery and the protection of the wound surface are not complete. In particular, in the case of an irregular wound which a portion of the skin is taken away, the adhesion is further reduced.
Korean Patent Publication No. 2011-0027434 discloses a composition for forming a water-repellent film with sustained drug delivery ability, comprising sodium fusidate, ethyl cellulose, soybean oil and ethanol. As mentioned above, the preparation having a high content of organic solvent causes pain upon application to the skin and reduces the rate of wound healing.
Korean Patent Publication No. 2002-0066024 discloses an ointment composition and film comprising water-soluble chitosan, chemically modified with water, and heparin as active substances.
Korean Patent No. 0440239 discloses a method for the preparation of hydrogels comprising polyvinyl alcohol, polyvinylpyrrolidone and chitosan. The composition has a high content of polymer and thus the water in the gel is not evaporated. Therefore, it cannot form a film.
Korean Patent Nos. 0608192 and 0644369 disclose technologies for producing sponges by freeze-drying dissolved chitosan. These technologies also do not form a film directly on the wound surface and thus the adhesion to the wound is reduced. Therefore, these technologies have the same problems as described above.
Korean Patent Publication Nos. 2012-0023653 and 2012-0022930 disclose medicinal creams comprising fusidic acid, sulphadiazine and chitosan as active substances as well as at least one of primary and secondary emulsifiers, wax, acid and water. These compositions contain a large amount of non-volatile, lipophilic and semi-solid materials such as paraffin, cetostearyl alcohol, etc. to give appropriate viscosity. However, the compositions disclosed in the above inventions have poor film formation properties, and even if the film is formed, it is easily destroyed by external mechanical stimuli.
The present inventors have intensively studied to overcome the drawbacks associated with the conventional preparations containing the above-described antibiotics. As a result, the present inventors invented a formulation which comprises an active substance, maintains the form of a gel during storage period, and forms a film upon application to a wound. We found that the composition of the present invention has a simpler configuration than the prior art, has excellent film-forming effect and high mechanical strength, and has excellent properties that form a film directly on a wound surface upon application to a wound site to provide high adhesion to the wound and to be easily removed from normal tissue of healed wound, thus completing the present invention.